Sustained release composition and method utilizing xanthan gum and an active ingredient

ABSTRACT

A compacted sustained release composition for delivering a drug as an active ingredient to the gastro-intestinal tract comprises an effective amount of the active ingredient in mixture with xanthan gum and an excipient, the active ingredient comprising in excess of 40 percent by weight of the total of the active ingredient and the xanthan gum, the mixture being in the form of a unit dose in capsule or tablet form. In addition to niacin, the active ingredient may be an analgesic, antipyretic, anti-inflammatory agent, vitamin, electrolyte replenisher, decongestant, antihistamine, and useful bacteriological organisms for the gastro-intestinal tract.

BACKGROUND OF THE INVENTION

This application is a continuation-in-part of co-pending applicationSer. No. 857,516, filed Mar. 25, 1992 now U.S. Pat. No. 5,292,534 issuedMar. 8, 1994.

This invention relates to a composition and method of manufacture anduse in which xanthan gum is combined with an active pharmaceutical orother ingredient in a compacted dose form for delivering the activeingredient to the gastro-intestinal tract over a sustained period.

Sustained or slow release compositions containing pharmaceuticalmedications or other active ingredients are designed to contain higherconcentrations of the medicament or ingredient and are prepared in sucha manner as to effect sustained or slow release into thegastro-intestinal digestive tract of humans or animals over an extendedperiod of time. Well absorbed oral sustained or slow release therapeuticdrug dosage forms have inherent advantages over conventional, immediaterelease dosage forms. The advantages include less frequent dosing of amedicament and resultant patient regime compliance, a more sustaineddrug blood level response, the possibility of effecting therapeuticaction with less ingested drug, and the mitigation of side effects. Byproviding a slow and steady release of the medicament over time,absorbed drug concentration spikes are mitigated or eliminated byeffecting a smoother and more sustained blood level response.

Many therapeutic agents, medicaments, or other active ingredients have awide window for absorption, meaning that the drug has been demonstratedto be well absorbed along the entire digest tract. Such agents,medicaments, or other active ingredients are then logical candidates forpossible dosage as a sustained or slow release medication.

Sustained or slow release therapeutic dose forms are based on many andvaried principles. For example, one of the techniques of preparationinvolves formation of the drug in generally spherical pellet formwherein a specific quantity of pellets are set aside for immediaterelease and the remaining drug pellets or spheres are coated withvarious thicknesses of a suitable fat, or resinous, or fatty resinouslike coating. When fractions of the pellets are blended together andthen filled into capsules or pressed into tablets, without destroyingthe integrity of the coatings, suitable slow or sustained release doseforms may be effected. Another technique is to admix the therapeuticagent with fats and solid polyhydric alcohols, such as polyoxyethyleneglycol, and/or a solid surfactant, such as polyoxyethylene glycoldistearate, and press the mixture into tablets to form an erosion matrixto effect slow or sustained release dosage forms. Another method employsthe use of a therapeutic agent bound to an ion exchange resin orotherwise complexed with an organic or inorganic molecule and imbeddedin a waxy core or granule and administered in capsule or pressed tabletform. Still another method employs the use of an indigestible filmformer such as methylcellulose applied to a powder or granule basecontaining a therapeutic agent followed by subsequent forming intocompressed tablets to effect slow or sustained release. Yet anothermethod employs a tablet containing a specific drug coated with anindigestible film in which the film is pierced by a laser beam to allowfor a small and precise portal from which the drug is slowly released.

As a result of the increased awareness of the importance ofhypercholesterolemia and its relationship to coronary heat diseaseduring the last several years, there has been an increased emphasis ontreatment with niacin (nicotinic acid). Guidelines for adults haverecently been published by the National Cholesterol Education Program,coordinated by the National Heart, Lung and Blood Institute, which statethat a desirable blood cholesterol level is below 5.17 mmol/liter.Approximately half of adults screened have been found to have a totalblood cholesterol level above the desired range, and accordingly, areencouraged to see a physician for further analysis and instruction. Ithas been recommended that clinicians use a bile acid sequesterant orniacin as first line therapy for treatment of hypercholesterolemicpatients. Niacin is also the oldest of the pharmacologic agents used inthe treatment of hyperlipidemia and, since its introduction in 1955, ithas been in continuous use either monadically, or in combination withbile acid binding resin therapy.

In doses of 3-6 g/day, which exceed its requirements as a B Vitamin,niacin (but not niacinamide) is highly effective in reducing elevatedlevels of plasma cholesterol and triglycerides. Niacin inhibits adiposetissue lipolysis, reduces plasma free fatty acid levels and decreasesvery low density lipoprotein synthesis, thereby decreasing theproduction of low density lipoproteins from the very low densitylipoproteins. Niacin is of demonstrated value in preventingmanifestations of arteriosclerotic heart disease, having been shown todecrease recurrent nonfatal myocardial infarction in the coronary drugproject by 40% without concurrent increase in mortality fromnonarteriosclerotic causes as has been observed with clofibrate.

Niacin is readily absorbed from the stomach and intestinal tract and hasno difficulty passing the tissue barrier. Following per osadministration of a tablet or capsule dosage of niacin peak plasmalevels are obtained within 15-30 minutes in humans. The drug is rapidlydistributed in the various tissues including kidney and adipose tissuewith a slower metabolism of liver and brown fat. Also of note is theobservation that niacin has the ability to penetrate the blood brainbarrier.

Niacin is rapidly eliminated from plasma and its elimination half-lifein humans is 20-45 minutes. Although large doses of 3-6 g/day of niacinare required to decrease circulating cholesterol and triglycerides inhumans, it does not appear that the high peak serum levels attained arerequired, since the lipid lowering effect is maintained after plasmaniacin levels are below the limit of sensitivity of the analyticalmethod used. Thus, there is no correlation between systemic levels ofniacin and its pharmacological effect.

The chief drawback to using niacin in the treatment of hyperlipidemia isfacial and truncal flushing, which occurs in nearly all users shortlyafter ingestion of tablets with as small a dosage as 75 mg of niacin pertablet. It appears that niacin induces flushing by increasing theformation and/or release of some prostaglandin, which in turn increasesthe production of cyclic amp. However, this mechanism does not appear tomediate the effect of niacin on lipolysis. The side effects of truncalflushing, nausea, gastro-intestinal upset, and rectal itchingexperienced following the ingestion of high potency niacin tablets (500mg/tablet) has contributed to patient dropout of niacin therapyintroduced to treat hyperlipidemia.

It has been difficult to produce a slow or sustained release niacinproduct by the conventional methods of barrier coating or erosion-typemechanisms. The classic concept of a sustained release dosage regimen isto release 20-35% of the therapeutic agent within the first hour and tosustain the remaining portion of the therapeutic agent over a 8-12 hourperiod. When one considers that the niacin therapeutic dose is 500-1000mg and that niacin will cause a flushing response in most subjects witha dosage release of more than 75 mg within a one hour period, theproblem becomes apparent. Nicobid, marketed by Armour Pharmaceuticals,has been the most widely marketed sustained release dose form of niacinin recent years. Clinical evaluations of the Nicobid dose form of 500 mgniacin per tablet indicate that the side effects have still not beenameliorated, and the main side effect of flushing is still responsiblefor a patient dropout rate approaching 20%. Therefore, some new methodof slow release is required to cope with the specific problem presentedby the niacin dose form requirements.

Bearing in mind the problems and deficiencies of the prior art, it istherefore an object of the present invention to provide a compositionand method of manufacture and use which delivers an activepharmaceutical or other ingredients in a dose form to thegastro-intestinal tract of humans and animals over a sustained period.

It is another object of the present invention to provide a compositionwhich delivers niacin, in large dose forms well above 75mg, to thegastro-intestinal tract without the side effects of flushing anditching.

It is a further object of the present invention to provide a sustainedrelease composition and method of manufacture and use which is usefulwith a wide number of active pharmaceutical and other ingredients.

It is yet another object of the present invention to provide acomposition which delivers active pharmaceutical and other ingredientsin which the active ingredients may be present in relatively largequantities compared to the remaining components of the composition.

SUMMARY OF THE INVENTION

The above and other objects, which will be apparent to those skilled inthe art, are provided in the present invention which relates to asimplified method of effecting a clinically validatable slow orsustained release of active pharmaceutical or other ingredients bycombining the active ingredient with xanthan gum, compacting thecombinate and size reducing the compact to form powders or capsules, orby combining the active ingredient with xanthan gum and a suitablelubricant and forming tablets by direct tablet compression techniques.

In one aspect, the invention comprises a compacted sustained releasecomposition for delivering a drug such as niacin as an active ingredientto the gastro-intestinal tract comprising an effective amount of theactive ingredient in mixture with xanthan gum, the active ingredientcomprising in excess of 40 percent by weight of the total of the activeingredient and the xanthan gum, the mixture being in the form of a unitdose in capsule or tablet form. The method corresponding to this aspectcomprises producing a compacted sustained release composition fordelivering a drug such as niacin as an active ingredient to thegastro-intestinal tract by mixing an effective amount of the activeingredient with xanthan gum, the active ingredient comprising in excessof 40 percent by weight of the total of the active ingredient and thexanthan gum, and forming the mixture in a unit dose in capsule or tabletform.

In another aspect, the invention comprises a compacted sustained releasecomposition for delivering a drug as an active ingredient to thegastro-intestinal tract comprising an effective amount of the activeingredient in mixture with xanthan gum, the active ingredient beingselected from the group consisting of analgesics, antipyretics,anti-inflammatory agents, vitamins, electrolyte replenishers,decongestants, antihistamines, and useful bacteriological organisms forthe gastro-intestinal tract, the mixture being in the form of a unitdose in capsule or tablet form. The method corresponding to this aspectcomprises producing a compacted sustained release composition fordelivering a drug as an active ingredient to the gastro-intestinal tractby mixing an effective amount of the active ingredient with xanthan gum,and forming the mixture in a unit dose in capsule or tablet form.

In a further aspect, the invention relates to a sustained releasecomposition for slow delivery of a drug as an active ingredient to thegastro-intestinal tract comprising an effective amount of the activeingredient, preferably niacin, in mixture with xanthan gum and anexcipient, the mixture being in the form of a unit dose in capsule ortablet form. The active ingredient is preferably present in an amount ofabout 40-80 weight percent, the excipient is preferably present in anamount of about 2-40 weight percent, and the xanthan gum is preferablypresent in an amount of about 20-50 weight percent, of the unit dose.The method corresponding to this aspect comprises producing a compactedsustained release composition for delivering a drug as an activeingredient to the gastro-intestinal tract by mixing an effective amountof the active ingredient with xanthan gum, and forming the mixture in aunit dose in capsule or tablet form.

The active ingredient(s) may be agglomerated with a water solublecarbohydrate based agglomerating agent prior to mixing with the xanthangum. Preferably, the mixture of active ingredient(s) and xanthan gum isdirectly compressed into unit dose tablets. Alternatively, the mixtureof active ingredient(s) and xanthan gum is compacted and reduced in sizeto fill unit dose capsules.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The sustained release mechanism of the present invention is based on theconcept of phoresis wherein the release rate of niacin or other activepharmaceutical or other ingredient is controlled by producing a tabletwhich forms a gel following ingestion. In order for the niacin or otheractive ingredient to be released to the gastro-intestinal tract in aslow and sustained manner, it is necessary for the ingredient to passuniformly and slowly through the gel. The release of the activecomponent through the gel mass is slow and steady and is controlled bythe amount of the gel former used to effect the system.

In accordance with the present invention, xanthan gum has been found tobe the most effective gel former used to produce the slow release ofniacin or other active ingredient in dose form. Xanthan gum is a highmolecular weight natural carbohydrate, or, more specifically, apolysaccharide. Xanthan gum defines the exocellular biopolysaccharidewhich is produced in a pure culture fermentation process by themicroorganism "Xanthomonas Campestris". In the fermentation,"Xanthomonas Campestris" is cultured in a well aerated medium containingcommercial glucose, a suitable nitrogen source, dipotassium hydrogenphosphate, and appropriate trace elements.

The polysaccharide coating formed surrounding the cell wall, xanthangum, must be stable and hydrophilic in order to protect the organismfrom dehydration during periods of adverse conditions. The polymerstructure, molecular weight, and gel forming characteristics of the cellwall coating are constant and reproducible under given conditions offermentation. At the conclusion of the fermentation process, xanthan gumis recovered by precipitation in isopropyl alcohol, then dried andmilled. The molecular weight of the xanthan gum polymer is probably inthe order of 2 million but has been reported to be as high as 13-50million. These reported differences are most probably due to associationphenomena between the polymer chains. The xanthan gum is preferablyobtained for processing in the present invention in dry, free flowinggranular or powder form, with a preferred particle size range of about20-200 U.S. Mesh (850-74 microns).

In accordance with the present invention, a clinically validarable slowor sustained release of active pharmaceutical or other ingredients isprepared by combining the active ingredient(s) with xanthan gum,compacting the combinate and size reducing the compact to form powdersor capsules, or, in a more preferred embodiment, by combining the activeingredient(s) with xanthan gum and a suitable lubricant and formingtablets by direct tablet compression techniques.

The active pharmaceutical or other ingredients which may be utilized incombination with xanthan gum include, in addition to niacin (nicotinicacid or 3-pyridine- carboxylic acid), any other pharmaceutical or drughaving a beneficial effect on the body when released to thegastro-intestinal tract in a slow or sustained manner. Preferably, theactive ingredient or agent is also provided in dry, free flowinggranular or powder form, with a preferred particle size range of about20-200 U.S. Mesh (850-74 microns). Such ingredients may be, for example,analgesic, antipyretic, and/or anti-inflammatory agents such as aspirin,acetamenophen and ibuprofen, vitamins such as pyridoxine (vitamin B-6)hydrochloride and cyanocobalamin (vitamin B-12), calcium ascorbate,electrolyte replenishers such as potassium chloride, decongestants suchas pseudoephedrine hydrochloride, antihistamines such aschlorpheniramine maleate, or useful bacteriological organisms for thegastro-intestinal tract such as lactobacillus acidophyllus.

The active ingredient or agent may be combined directly with the xanthangum, as will be described below, or may be preliminarily combined with alow density, highly porous, generally spherical, water solublecarbohydrate-based agglomerates of maltodextrin, dextrose, sucrose,fructose, lactose or other agglomerated corn syrup solid, for example.Any of the water soluble carbohydrate-based agglomerate may beco-agglomerated with each other prior to or during combination with theactive ingredient.

The preferred agglomerate is maltodextrin, a low conversion starchhydrolyzate having a D.E. (dextrose equivalent) less than 20, an examplebeing VELite 1000 maltodextrin available from Valentine Enterprises,Inc. of Lawrenceville Georgia comprised of Maltrin M-100 maltodextrinavailable from Grain Processing Corp.

In addition to the water soluble carbohydrate-based agglomeratesdescribed above, the active ingredient and xanthan gum may be combinedwith other water soluble carbohydrate excipients to form the final dry,free flowing, granular product. By the term "excipients" is meantsubstances or ingredients generally used in the drug or food industrywhich do not alter the character and function of the combination ofactive ingredient and xanthan gum. Other useful excipients includemannitol, sorbitol, milk solids, and their derivatives. These excipientsmay be present in an amount of up to 40% by weight, preferably about2-20% by weight, of the total mixture.

When the active ingredient is to be preliminarily combined with thewater soluble carbohydrate-based agglomerate or other excipient, thecomponents are preferably agglomerated in a fluid bed agglomerator bystandard spray granulation techniques. The active ingredient is combinedwith water soluble carbohydrate-based agglomerate or excipient andproduced as dry, free flowing granules of a desired particle size, forexample, about 20-100 U.S. mesh (850-149 microns). The importantcharacteristic is that the active ingredient is contained in or on thecarbohydrate-based agglomerate and is immediately available, and isstable in the formulation with the xanthan gum. No coatings such as waxor other compositions are placed over the active ingredient which wouldinterfere with dissolution of the active ingredient. It has beendiscovered that xanthan gum alone may be employed in the final productto effect slow and sustained release in the body.

After the active ingredient is provided in its desired form, either asessentially pure granules or in the agglomerated form described above,it is admixed with the desired amount of xanthan gum and optionally, oneor more excipients, preferably by low shear mixing such as thatencountered in a planetary, ribbon or plow mixer. The relative amountsof active ingredient and xanthan gum may be varied as desired. It hasbeen unexpectedly discovered that a considerably higher amount of activeingredient, particularly niacin, may be employed relative to the xanthangum while still retaining the desired effect of slow and sustainedrelease in the gastro-intestinal tract of humans or animals. Inparticular, the mixture may employ in excess of 40% by weight of activeingredient, and even a major amount of active ingredient, in the finaldose form, whether it be in compacted and reduced to powder for fillingin capsules or directly compressed into tablet form. In the case ofniacin as the active ingredient, this is a considerably higher relativeamount than can be employed when another gum, such as guar gum, isemployed, where limits of 33% by weight of niacin have been reported. Inthe present invention, the amount of active ingredient may morepreferably range from 50-80% by weight of the total mixture, and theamount of xanthan gum is preferably not less than 20% by weight, morepreferably from 20-50% by weight of the total composition. The amount ofexcipient(s) may comprise from 2-40% by weight of the total composition.

After the mixing process, the mixture of active ingredient, xanthan gumand, optionally, excipient(s) is compacted and size reduced, and thenmade into desired unit dose form such as filled capsules. Compaction maybe by standard techniques such as slugging where tablets are pressed orby roller compaction. In either case, the compacted tablets or rollcompactions of the mixture are ground to reduce the particle size of themixture, e.g., to a particle size of about 20-100 U.S. mesh (850-149microns), and then filled into the final capsule or powder blend doseform. Preferably, to achieve best sustained release characteristics, themixture may be directly compressed by standard techniques into finaltablet dose form. A lubricant such as stearic acid may be added in anamount of 0.1-5% by weight of the total composition to assist in thetableting process.

By following the process of the present invention to produce tablets inthe form described, 1000 mg doses of niacin have been able to beformulated in tablets containing xanthan gum in the ranges specified andingested by humans without a flushing response. Since as little as 75mg/hr. of niacin has been shown to produce flushing, this indicates thatthe present invention is able to deliver the niacin in slow and/orsustained quantities over as much as 24 hours or more.

It is theorized that an important function of xanthan gum in the presentinvention is control of aqueous fluid rheology. It has been found thatconcentrated aqueous solutions of xanthan gum exhibit extremepseudo-plasticity. The xanthan gum/active ingredient tablet dose forms agel sol (a hydrated gel) when exposed to the environment in the stomach.It is believed that when intestinal shear stress is applied to thesolvated tablet dose form the viscosity of the xanthan gum gel isreduced and concomitantly spread to allow the drug niacin to phorese orpass through the gel mass.

Once the xanthan gum/active ingredient tablet enters the digestive tractit is subjected to the shear forces of the digestive action and movementwhich are believed to be sufficient enough to reach the yield point ofthe xanthan gel sol. The yield point of the xanthan gum sol can beconsidered to be the quantity of force required to dissociate some ofthe "super junction zones" of the xanthan gum and the shear thinningthat results allows for the spread of the gel sol.

A principal advantage of xanthan over other gums such as guar gum is itsgreater purity, its lot-to-lot uniformity of composition, and itsresistance to enzymatic cleavage in the digestion tract. It is alsobelieved to be safe as in reported studies, quantities of 12 g/day ofxanthan gum were ingested each day for a period of 12 weeks with nosevere adverse digestive symptoms. In another study, following a 7-daycontrol period, 5 male volunteers consumed, on each of 23 consecutivedays, a weight of xanthan gum equal to 15 times the current acceptabledaily intake of 10 mg/kg body weight, as approved by the EEC and by thejoint FAO/WHO Expert Committee on Food Additives. Measurements beforeand at the end of the test period showed that the ingestion of xanthan,as a prehydrated gel, acted as a bulking agent in terms of its effectson fecal wet and dry weight and intestinal transit times but had nosignificant effect on plasma biochemistry. Haematological indices,urinalysis parameters, glucose tolerance and insulin tests, serumimmunoglobulins, triglycerides, phospholipids and high densitylipoproteins, breath hydrogen and breath methane concentrations. Therewas, however, a moderate (10%) reduction in serum cholesterol and asignificant increase in fecal bile acid concentrations. The dataindicate that the ingestion of xanthan caused no adverse dietary norphysiological effects in any of the test subjects. In particular, all ofthe enzymatic and other parameters that act as sensitive indicators oradverse toxicological effects remained unchanged.

Positive effects of xanthan ingestion are believed to be its lack oftoxicity and also its ability to bind or otherwise increase bile acidcontent in the feces. It is obvious that any increase in bile acid inthe stool will have a positive effect when dealing with hyperlipidemia.Even though the test quantities were of a high level, it is apparentthat the effect of bile acid elimination and the non formation of freefatty acids is a desirable effect even when the quantities of xanthanare relatively limited.

One additional clinical observation on the use of xanthan gum in obesitycan shed some additional light on the use of smaller quantities ofxanthan gum to modify serum lipidology. Body weight and cholesterol andtriglycerides in blood were estimated in 2 groups of 10 women, 20 to 50years of age, with body mass index of 30-40 before and 30-60 daysfollowing ingestion of 2 550 mg capsules of xanthan gum with 250 ml ofwater 3 times per day or starch placebo capsules with 250 ml of water 3times per day. In each case the capsules were administered before meals.After 30 and 60 days of treatment with xanthan gum body weight decreasedby 2.9 and 7.7 kg, cholesterol by 18.8 and 20.5 and triglycerides by12.9 and 15.5 mg/100 ml, respectively. Differences were significantcompared with the placebo group. There was also a significant sensationof satiety at 90 min, and at 5 hours after each meal with those subjectson the xanthan gum regimen. Even at this level (3 gm xanthan gum/day),significant serum lipid changes were apparent.

EXAMPLES

The following illustrative examples are given to more particularlyillustrate the specific details of the practice of the presentinvention. Equivalent procedures and quantities will occur to thoseskilled in the art and, therefore, the following examples are not meantto define the limits of the present invention, these being defined bythe appended claims. All references to percentages in the examples, asthroughout the specification, are to weight percentage, unless otherwiseidentified.

Example 1

Examples of successful niacin/xanthan gum tablet formulations and theirmethod of preparation are as follows:

    ______________________________________                                        Formulation No. VL5-079                                                       ______________________________________                                        Niacin Base Granulation:                                                      Niacin (Nicotinic Acid) Roche                                                                      97.0%                                                    Maltodextrin M-100   3.0%                                                     ______________________________________                                    

The niacin was charged into a fluid bed agglomerator and themaltodextrin was sprayed over as a 15% aqueous solution to effectagglomeration and compressibility with concomitant good flowcharacteristics. The final granulation was sized -20 mesh, U.S. sievesize.

    ______________________________________                                        Formulation No. VL5-080C                                                      ______________________________________                                        Niacin Base Granulation                                                                           61.9%                                                     (No. VL5-079)                                                                 Xanthan Gum (Keltrol SF)                                                                          37.4%                                                     Stearic Acid        0.7%                                                      ______________________________________                                    

The components were well mixed and compressed on caplet punches at aweight of 840 mg/tablet at a hardness of 12 kp.

    ______________________________________                                        Each 840 mg Tablet yields:                                                                      Niacin      504.4  mg                                                         Xanthan Gum 314.2  mg                                                         Stearic Acid                                                                              5.9    mg                                                         Maltodextrin                                                                              15.5   mg                                       1 × 840 mg Tablet 3×/day                                                            Niacin      1500   mg                                       yields:           Xanthan Gum 942    mg                                       2 × 840 mg Tablets 3×/day                                                           Niacin      3000   mg                                       yields:           Xanthan Gum 1882   mg                                       3 × 840 mg Tablets 3×/day                                                           Niacin      4500   mg                                       yields:           Xanthan Gum 2824   mg                                       ______________________________________                                    

This formulation was used in tests with subjects to evaluate flushing.No adverse effects have been noted dosing two tablets.

The quantity or percentage composition relative to the xanthan gum hasbeen raised and lowered from the base formulation (VL5-080C). The leastxanthan quantity that has, up until now, produced no flushing is notedbelow.

    ______________________________________                                        Formulation No. VL5-117E                                                      ______________________________________                                        Niacin Base Granulation                                                                           76.4%                                                     (No. VL5-079)                                                                 Xanthan Gum (Keltrol SF                                                                           22.7%                                                     Stearic Acid        0.9%                                                      ______________________________________                                    

The materials were mixed and compressed into tablets having a weight of680 mg at a hardness of 12 kp.

Single tablet trials resulted in no adverse flush reaction.

Comparative Example 1

Utilizing the procedure to make the base formulation, No. VL5-080C, thexanthan gum was replaced with guar gum. After ingestion in testsubjects, flushing was found to occur relatively quickly (within 2-3hours). When half of the xantham gum was replaced with guar gum,flushing occurred after 2 hours. Based upon the trials employed, theeffect of slow release of niacin appears to be due to the presence ofthe xanthan gum and that mixed gum systems of xanthan and guar gum arenot as effective.

Results similar to those experienced with guar gum can also bedemonstrated with the use of locust bean gum. It appears that guar andlocust bean gums are labile to the enzymatic digestive mode. A mixedsystem of niacin with approximately equal amounts of either guar gum orlocust bean gum and xanthan gum results in flushing approximately 2hours after ingestion of the slow release niacin tablets. Xanthan gum isbelieved to be better able to resist enzymatic digestion, liquefication,or in some other manner of destruction of the gel structure than eitherthe guar gum or the locust bean

Example 2

    ______________________________________                                        FORMULATION No. VL4-081                                                       ______________________________________                                        Niacin was agglomerated in a Freund Mini Flow Coater fluid bed                agglomerator as follows:                                                      In Bed:                                                                       Niacin                      400    gm                                         (Lump Free in Fine Powder)                                                    In Solution:                                                                  Maltrin M-100 (GPC)         12.5   gm                                         Water                       112.5  gm                                         Flow Control @ 55%                                                            Air for atomization 10 PSI (Coarse)                                           Spray Rate @ 3.5                                                              Spray @ 1 Minute                                                              Pulse Jet @ .1 & .1                                                           Air Inlet 80 C                                                                Terminal Dry @ 42 C                                                           Total solution overall will yield 97% niacin agglomerates                     Pass agglomerates through 20 mesh                                             ______________________________________                                    

The agglomerates from No. VI4-079 were then blended with xanthan gum asfollows:

    ______________________________________                                        Niacin Base Granulation                                                                           61.9%                                                     Xanthan Gum (Keltrol Gm)                                                                          37.4%                                                     (coarse granule)                                                              Stearic acid (fine powder)                                                                        0.7%                                                      ______________________________________                                    

Blend the materials for 10 minutes then compress on capsule shapepunches at 840 mg/tablet at maximum pressure (18-20 KP).

    ______________________________________                                        Each tablet yields:                                                           Niacin               504.4  mg                                                Xanthan Gum          314.2  mg                                                Maltrin M-100        15.5   mg                                                Stearic acid         5.9    mg                                                Total Tablet Weight  840.0  mg                                                Tablet Weight Specification                                                                        840.0  mg + 3%                                           (Average weight 10 tablets)                                                                        (840   mg-885 mg)                                        2 tablets 3×/day yields:                                                Niacin               3,000  mg/day                                            Xanthan Gum          1,884  mg/day                                            ______________________________________                                    

After taking the aforementioned doses of two niacin tablets, three timesper day, the test subjects showed no flushing. All of the test subjectsshowed satisfactory recovery of niacin and nicotinuric acid from urine.

Thus, the combinate of xanthan gum and niacin provides a therapeuticdose form that obviates the flushing reaction associated with largedoses of niacin. While flush response is usually triggered byapproximately 75 mg of niacin, in the combinate of the presentinvention, we are able to provide dose quantities of niacin of 1000 mgwithout a flushing response.

Example 3

Agglomerated/granulated niacin base was prepared in a Freund Model 80fluid bed agglomerator according to the following formulation:

    ______________________________________                                        In Product Container:                                                         Niacin Powder U.S.P.    40     kg                                             Pump Solution:                                                                10 D.E. Maltodextrin Maltrin M-100                                                                    1.23   kg                                             (Grain Processing Corp.)                                                      Distilled Water         11.07  kg                                             Atomizing gun pressure  3.0    atm                                            Atomizing air volume    150    m.sup.3 /hr                                    Pattern air volume      20     m.sup.3 /hr                                    ______________________________________                                    

The product bowl was secured and fluidization was initiated with inletair at 80° C. Alternate spraying and shaking of the filters to returnun-agglomerated fines to the bowl was continued until all of the pumpsolution was delivered to the fluidized bed. The product was dried,removed, and sized to -20 mesh and packaged.

A blend for tableting was prepared as follows:

    ______________________________________                                        Agglomerated Niacin   61.9%                                                   Xanthan Gum (TIC)     37.4%                                                   Stearic acid (fine powder U.S.P.)                                                                   0.7%                                                    ______________________________________                                    

8.0 kg of the prepared blend for tableting was compressed on capletshaped punches at a weight of 840 mg/tablet, with each tablet containing540 mg of niacin.

A crossover clinical study indicated that the formulation is effectivein cholesterol lowering and was essentially flush response free.

Example 4

Tablets were prepared as follows:

    ______________________________________                                        Compression granulated                                                                              60.0%                                                   Niacin (Lonza) U.S.P.                                                         Xanthan Gum (Kelco K-7B170)                                                                         39.3%                                                   Stearic Acid N.F (fine powder)                                                                      0.7%                                                    ______________________________________                                    

The components were mixed and blended to effect a product suitable forcompression.

Tablets were compressed on capsule shaped punches and dies at a weightof 840 mg to yield tablets containing 504 mg niacin per tablet.

A 6 patient availability indicated satisfactory recovery with noflushing following a 2 tablet dose.

Example 5

Tablets were prepared as follows:

    ______________________________________                                        Niacin fine powder U.S.P. (Roche)                                                                   50.0%                                                   Xanthan Gum (fine powder)                                                                           49.3%                                                   Stearic Acid (fine powder U.S.P.)                                                                   0.7%                                                    ______________________________________                                    

6.0 kg of material were blended and further granulated by compaction toyield 20-60 mesh granules. The granules were filled into two piece hardgelatin capsules at a fill weight of 450 mg and contained 225 mg niacinper capsule.

In a 6 patient evaluation, urinary tracing indicated satisfactoryrelease of the niacin. Two capsule and four capsule dosing equivalent to500 and 1000 mg niacin per dose indicated no flushing.

Other active ingredients were tested as follows:

Example 6

A tableting base was mixed from the following components:

    ______________________________________                                        Acetamenophen (coarse granular)                                                                     65.0%                                                   Xanthan Gum (granular)                                                                              34.3%                                                   Stearic Acid N.F. (fine powder)                                                                     0.7%                                                    ______________________________________                                    

A 5 kg blend of the tableting base was prepared and pressed into tabletsat a weight of 770 mg per tablet equivalent to 500 mg acetamenophen pertablet.

Example 7

A tableting base was mixed from the following components:

    ______________________________________                                        Aspirin (coarse crystals)                                                                          61.9%                                                    Xanthan Gum (Keltrol)                                                                              37.4%                                                    Stearic acid N.F. (fine powder)                                                                    0.7%                                                     ______________________________________                                    

A 10 kg blend of the tableting base was prepared and pressed intotablets at a weight of 815 mg per tablet equivalent to 500 mgacetylsalicylic acid per tablet.

Example 8

A tableting base was mixed from the following components:

    ______________________________________                                        Ibuprofen powder     60.0%                                                    Xanthan Gum (Keltrol)                                                                              39.3%                                                    Stearic acid N.F. (fine powder)                                                                    0.7%                                                     ______________________________________                                    

A 5 kg of the tableting base was prepared and pressed into tablets at aweight of 667 mg per tablet equivalent to 400 mg ibuprofen per tablet.

Example 9

A tableting base was mixed from the following components:

    ______________________________________                                        Potassium chloride USP                                                                             60.0%                                                    (fine crystals)                                                               Xanthan Gum (Ketrol) 39.3%                                                    Stearic acid N.F. (fine powder)                                                                    0.7%                                                     ______________________________________                                    

A 5 kg blend of the tableting base was prepared and pressed into tabletsat a weight of 834 mg equivalent to 500 mg of potassium chloride pertablet.

Example 10

A tableting base was mixed from the following components:

    ______________________________________                                        Lactobacillus Achidophylluss                                                                        50.0%                                                   (4 billion organisms/gm)                                                      Xanthan Gum powder (Keltrol)                                                                        49.3%                                                   Stearic acid N.F. (fine powder)                                                                     0.7%                                                    ______________________________________                                    

A 1 kg blend of the tableting base was prepared and pressed into tabletsat a weight of 500 mg equivalent to 250 mg of lactobacillus acidophyllusculture per gm (1 billion organisms.)

Example 11

A tableting base was mixed from the following components:

    ______________________________________                                        Acetamenophen        54.8%                                                    Chlorpheniramine Maleate                                                                           0.6%                                                     Pseudoephedrine HCl  4.6%                                                     Xanthan Gum          39.3%                                                    Stearic acid N.F. (fine powder)                                                                    0.7%                                                     ______________________________________                                    

A 1 kg blend of the tableting base was prepared and pressed into tabletsat a weight of 650 mg. The tablets were equivalent to:

    ______________________________________                                        Acetamenophen       356 mg                                                    Chlorpheniramine Maleate                                                                           30 mg                                                    Pseudoephedrine HCl  4 mg                                                     ______________________________________                                    

Example 12

A tableting base was mixed from the following components:

    ______________________________________                                        Calcium Ascorbate    65.0%                                                    Xanthan Gum          34.3%                                                    Stearic acid N.F. (fine powder)                                                                    0.7%                                                     ______________________________________                                    

A 1 kg blend of the tableting base was prepared and pressed into tabletsat a weight of 900 mg/tablet. Each tablet was equivalent to 585 mg ofascorbic acid.

Example 13

A tableting base was mixed from the following components:

    ______________________________________                                        Pyridoxine HCl/Maltodextrin                                                                        65.0%                                                    Co-agglomerate                                                                Xanthan Gum          34.3%                                                    Stearic acid N.F. (fine powder)                                                                    0.7%                                                     ______________________________________                                    

A 1 kg blend of the tableting base was prepared and pressed into tabletsat a weight of 650 mg/tablet. Each tablet was equivalent to 50 mg ofpyridoxine hydrochloride.

Example 14

A tableting base was mixed from the following components:

    ______________________________________                                        Cyanocobalamine/Maltodextrin/                                                                       65.0%                                                   Dextrose Co-agglomerate                                                       Xanthan Gum           34.3%                                                   Stearic acid N.F. (fine powder)                                                                     0.7%                                                    ______________________________________                                    

A 1 kg blend of the tableting base was prepared and pressed into tabletsat a weight of 650 mg/tablet. Each tablet was equivalent to 75 mg ofcyanocobalamine (vitamin B-12).

The compositions incorporating xanthan gum in the foregoing examples6-14 exhibit satisfactory sustained release of the active ingredientstherein into the gastro-intestinal tract.

It will thus be seen that the objects set forth above, among those madeapparent from the preceding description, are efficiently attained and,since certain changes may be made in the above constructions withoutdeparting from the spirit and scope of the invention, it is intendedthat all matter contained in the above description shall be interpretedas illustrative and not in a limiting sense.

While this invention has been illustrated and described in what areconsidered to be the most practical and preferred embodiments it will berecognized that many variations are possible and come within the scopethereof, the appended claims therefore being entitled to a full range ofequivalents.

Thus, having described the invention, what is claimed is:
 1. A sustainedrelease composition for slow delivery of a drug as an active ingredientto the gastro-intestinal tract consisting essentially of an effectiveamount of said active ingredient in mixture with xanthan gum and anexcipient, the mixture being in the form of a unit dose in capsule ortablet form, said active ingredient being present in an amount of about40-80 weight percent of said unit dose, said excipient being present inan amount of about 2-40 weight percent of said unit dose, and saidxanthan gum being present in an amount of about 20-50 weight percent ofsaid unit dose.
 2. The composition of claim 1 wherein said xanthan gumcomprises no more than 60% by weight of the total of said activeingredient and said xanthan gum.
 3. The composition of claim 1 includinga lubricant.
 4. The composition of claim 1 wherein said activeingredient is selected from the group consisting essentially ofanalgesics, antipyretics, anti-inflammatory agents, vitamins,electrolyte replenishers, decongestants, antihistamines, and usefulbacteriological organisms for the gastro-intestinal tract.
 5. Thecomposition of claim 1 wherein said composition comprises a major amountby weight of niacin and a minor amount of xanthan gum.
 6. Thecomposition of claim 1 wherein said excipient is a water soluble,carbohydrate-based agglomerate.
 7. The composition of claim 1 whereinsaid active ingredient comprises a major amount of said unit dose. 8.The composition of claim 1 wherein said active ingredient is selectedfrom the group consisting of aspirin, acetamenophen, ibuprofen,pyridoxine (vitamin B-6) hydrochloride, cyanocobalamin (vitamin B-12),calcium ascorbate, chlorpheniramine maleate, potassium chloride,pseudoephedrine hydrochloride and lactobacillus acidophyllus.
 9. Amethod of producing a sustained release composition for slow delivery ofa drug as an active ingredient to the gastro-intestinal tract consistingessentially of mixing an effective amount of said active ingredient withxanthan gum and an excipient, said active ingredient being present in anamount of about 40-80 weight percent of said mixture, said excipientbeing present in an amount of about 2-40 weight percent of said unitdose, and said xanthan gum being present in an amount of about 20-50weight percent of said mixture; compacting the mixture; and forming themixture into a unit dose in capsule or tablet form.
 10. The method ofclaim 9 wherein said xanthan gum comprises no more than 60% by weight ofthe total of said active ingredient and said xanthan gum.
 11. The methodof claim 9 including the step of adding a lubricant prior to forming themixture into a unit dose in capsule or tablet form.
 12. The method ofclaim 9 wherein said active ingredient is selected from the groupconsisting essentially of analgesics, antipyretics, anti-inflammatoryagents, vitamins, electrolyte replenishers, decongestants,antihistamines, and useful bacteriological organisms for thegastro-intestinal tract.
 13. The method of claim 9 wherein saidcomposition comprises a major amount by weight of niacin and a minoramount of xanthan gum.
 14. The method of claim 9 including the step offorming an agglomerate of said active ingredient with a water soluble,carbohydrate-based agglomerate prior to mixing with said xanthan gum.15. The method of claim 9 wherein said active ingredient comprises amajor amount of said unit dose.
 16. The method of claim 15 wherein saidactive ingredient is selected from the group consisting of aspirin,acetamenophen, ibuprofen, pyridoxine (vitamin B-6) hydrochloride,cyanocobalamin (vitamin B-12), calcium ascorbate, chlorpheniraminemaleate, potassium chloride, pseudoephedrine hydrochloride andlactobacillus acidophyllus.
 17. A sustained release composition for slowdelivery of niacin as an active ingredient to the gastro-intestinaltract consisting essentially of an effective amount of niacin in mixturewith xanthan gum and an excipient, the mixture being in the form of acompacted unit dose, said niacin being present in an amount of about40-80 weight percent of said unit dose, said excipient being present inan amount of about 2-40 weight percent of said unit dose, and saidxanthan gum being present in an amount of about 20-50 weight percent ofsaid unit dose.
 18. The composition of claim 17 wherein said xanthan gumcomprises no more than 60% by weight of the total of said niacin andsaid xanthan gum.
 19. The composition of claim 17 including a lubricant.20. The composition of claim 1 wherein said excipient is a watersoluble, carbohydrate-based agglomerate.
 21. A method of producing asustained release composition for slow delivery of niacin as an activeingredient to the gastro-intestinal tract consisting essentially ofmixing an effective amount of niacin with xanthan gum and an excipient,said niacin being present in an amount of about 40-80 weight percent ofsaid unit dose, said excipient being present in an amount of about 2-40weight percent of said unit dose, and said xanthan gum being present inan amount of about 20-50 weight percent of the mixture; compacting themixture; and forming the mixture into a unit dose.
 22. The method ofclaim 21 wherein said xanthan gum comprises no more than 60% by weightof the total of said niacin and said xanthan gum.
 23. The method ofclaim 21 including the step of adding a lubricant prior to the step offorming the mixture into a unit dose in capsule or tablet form.
 24. Themethod of claim 9 including the step of forming an agglomerate of saidactive ingredient with a water soluble, carbohydrate-based agglomerateprior to mixing with said xanthan gum.